Electrospray ionization (ESI) technology allows ions to be produced from a liquid solution and introduced into an analytical device such as a mass spectrometer. Typically, an aerosol is produced in a spray chamber of the analytical device by passing a fluid sample through a capillary such that the capillary serves as an electrospray emitter and has a terminus subjected to an electric field within the chamber. The electric field is usually generated by placing a source of electrical potential, e.g., an electrode or sample introduction orifice, near the capillary terminus, wherein the source is held at a voltage potential difference with respect to the capillary terminus. As a result, a large electric potential gradient is created at the terminus of the electrospray emitter.
The emitter may be operated in a positive or negative ion mode by creating a negative or positive potential gradient, respectively. In the positive-ion mode of operation, a high positive voltage is applied to the electrospray emitter and/or a high negative voltage at the electrode or sample introduction orifice. In such case, the imposed field will penetrate the liquid at the capillary tip and the accumulated positive charge at the surface leads to destabilization of the surface to form a cone (Taylor cone), because the positive ions are drawn down but cannot escape from the liquid. At a sufficient high field, bulk liquid from the Taylor cone may be broken into charged liquid droplets. Alternatively, a thin stream may be formed carrying liquid away from the Taylor cone before the stream is broken up into droplets. In either case, these droplets migrate from the positive emitter towards the mass spectrometer inlet. The droplets undergo solvent evaporation and fission, which allows the generation of gas phase ions. The ions are then introduced into mass spectrometer's vacuum and are subjected to mass spectrometric analysis. Analogously, in the negative-ion mode of operation, the electric field is reversed and the charge of the gas phase ions formed as a result is reversed as well.
The performance of an electrospray emitter is limited in large part by its overall geometry, which in turn is determined by the technique used to fabricate the emitter. For example, several different types of electrospray emitters for use in low flow rate mass spectrometry include a glass tip that is formed by heating and pulling a glass capillary. As a result of such stretching, the outer and inner diameters of such capillaries are decreased.
Additional electrospray emitter shaping techniques include, e.g., mechanical machining methods. Such methods suffer from a number of drawbacks such as low output and inferior dimensional control. While semiconductor surface micromachining fabrication techniques have been proposed, such techniques are not suitable for producing an emitter that protrudes from a lateral surface of a substantially planar device.
Currently, microdevices employing microfluidic technology are used as chemical analysis and clinical diagnostic tools. Sample preparation, separation and detection compartments have been proposed to be integrated on such devices. In general, the small size of microdevices allows for the analysis of minute quantities of a fluid sample, which is an advantage when the sample is expensive or difficult to obtain. See, e.g., U.S. Pat. No. 5,500,071 to Kaltenbach et al., U.S. Pat. No. 5,571,410 to Swedberg et al., and U.S. Pat. No. 5,645,702 to Witt et al. In addition, such microfluidic technologies may operate at extreme low flow rates, e.g., in the nanoflow regime. This tends to increase mass spectrometry sensitivities.
Many have attempted to incorporate electrospray technology in such microdevices. One such effort to interface a microdevice with a mass spectrometer involves providing an outlet on an unbounded surface of a microdevice from which fluid sample is dispersed. See, e.g., U.S. Pat. No. 5,872,010 to Karger et al. and Ramsey et al. (1997), “Generating Electrospray from Microchip Devices Using Electoosmotic Pumping,” Anal. Chem. 69: 1174-78. This approach is problematic because it tends to require a larger sample volume, lower ionization efficiency, and/or compromise band resolution emerging from the outlet port. It has been observed that a sharp emitter with a small outside diameter and a smooth rim is generally desired for increasing stability of electrospray ionization, especially at a low sample flow rate.
Several approaches have been reported for integrating electrospray tips onto microdevices. For example, an electrospray emitter formed separately from a microdevice for subsequent attachment. See, e.g., International Patent Publication No. WO 00/022409; Figeys et al. (1997), “A Microfabricated Device for Rapid Protein Identification by Microelectrospray Ion Trap Mass Spectrometry,” Anal. Chem. 69:3153-60; Zhang et al. (1999), “A Microfabricated Devices for Capillary Electrophoresis-Electrospray Mass Spectrometry,” Anal. Chem. 71:3258-64; Li et al. (2000), “Separation and Identification of Peptide from Gel Isolated Membrane Proteins Using a Micromachined Device for Combined Capillary Electrophoresis,” Anal. Chem. 72:799-809; and Zhang et al. (2000), “A Microdevice with Integrated Liquid Junction for Facile Peptide and Protein Analysis by Capillary Electrophoresis/Electrospray Mass Spectrometry,” Anal. Chem. 72:1015-22. However, the likelihood of success in implementing this approach depends greatly on the quality of the attachment operation, and the interface formed between the emitter and the microdevice.
Micromachined electrospray emitters have been produced from silicon-based microdevices (see, e.g., International Patent Publication No. WO 98/35376 and Schultz et al. (1999) “A fully integrated monolithic microchip-based electrospray device for microfluidic separations,” 47th ASMS Conference on Mass Spectrometry and Allied Topics, June 13-17) and from Parylene-based microdevices (see, e.g., Licklider et al. (2000), “A Micromachined Chip Based Electrospray Source for Mass Spectrometry,” Anal. Chem. 72:367-75. However, these approaches also suffer from a number of drawbacks. For example, while silicon ESI emitters can be made with very small tip diameters, integration of such emitters to additional microdevice functionalities can be difficult and costly. In addition, while Parylene processing costs tend to be significantly lower than silicon processing costs, dimensional and geometrical control over Parylene-based emitters is lacking compared to silicon-based emitters.
Laser ablation may be used to form features of microdevices such as those described in U.S. Pat. No. 6,459,080 to Yin et al. For example, commonly owned U.S. patent application Ser. No. 09/711,804 entitled “A Microdevice Having an Integrated Protruding Electrospray Emitter and a Method for Producing the Microdevice,” inventors Brennen, Yin, and Killeen, filed on Nov. 13, 2000, describes a method for shaping a polymeric microdevice that involves removing material through a non-mechanical technique, e.g., laser ablation. As a result of material removal, an exterior microdevice surface is formed having an integrated electrospray emitter protruding therefrom. The emitter may be shaped to facilitate the formation of a low volume Taylor cone from the sample emerging from the sample outlet port under influence of an electric field.
While laser ablation is an effective technique for removing material from polymeric microdevices to form ESI emitters, there is a limit to the degree to which the geometric dimensions of emitters may be controlled. Generally, it is difficult to form ESI emitters having an extremely small-diameter tip by removing material from polymeric materials through the use of laser ablation alone. When emitters having uncontrolled geometries are placed in operation, unstable Taylor cones may be formed, especially at low flow rates and at low solvent concentrations.
Thus, there is a need and a desire to improve the performance of microdevices having integrated ESI emitters by providing an improved method for controlling the geometry and dimensional tolerances of the emitters.